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Background: Follicular lymphoma (FL) is one of the most immune-responsive of all cancers. However, immunosuppressive mechanisms in the tumor microenvironment may impair optimal antitumor immune responses. Expression of programmed death (PD)-1, a coinhibitory receptor, is markedly increased on intratumoral T cells in FL and is associated with impaired T-cell function. CT-011 (pidilizumab), a humanized anti-PD-1 monoclonal antibody, blocks the PD-1/PD-ligand pathway, and can enhance the function of antitumor T cells and NK cells. Rituximab, the monoclonal anti-CD20 antibody, acts in part via activation of NK cell-mediated antibody-dependent cellular cytotoxicity. Therefore, the combination of CT-011 and rituximab may have additive and/or synergistic effects via activation of both innate (NK cells) and adaptive (T cells) arms of the immune system and enhance clinical efficacy without increasing toxicity. We conducted a single arm phase II trial to determine the safety and efficacy of CT-011 and rituximab in patients (pts) with relapsed FL.

Methods: Pts with rituximab-sensitive, grade 1–2 FL relapsed after 1-4 prior therapies with measurable disease, adequate organ function, and absolute lymphocyte count of ≥ 0.6×109/L were eligible for enrollment. Pts with HIV, hepatitis B or C, and history of autoimmune diseases or allogeneic stem cell transplantation were excluded. CT-011 was dosed at 3 mg/kg IV every 4 weeks (wks) for 4 infusions and rituximab was dosed at 375 mg/m2 IV weekly for 4 wks starting 2 wks after the first infusion of CT-011. Pts with complete response (CR), partial response (PR), or stable disease (SD) received 8 additional optional infusions of CT-011 every 4 wks (for a total of 12). Pts were evaluated for response by CT scans and/or PET after 2 and 4 infusions of CT-011 and every 3 months (mo) thereafter for up to 2 yrs. Bone marrow biopsy was performed to confirm CR when appropriate. Blood and tumor samples were collected to assess the effect of CT-011 on immune cells and are reported separately. The primary objective was to determine the overall response rate (ORR). The secondary objectives were to determine the safety and toxicity, CR rate, progression-free survival (PFS), effect of CT-011 on T and NK cells, and to evaluate the immunogenicity and pharmacokinetics of CT-011. The combination was estimated to induce an ORR of at least 60% as compared to an ORR of 40% with rituximab retreatment (Davis et al, J Clin Oncol, 2000). A sample size of 30 was estimated to be adequate for this purpose.

Results: Of the 30 pts enrolled and treated on the study, one pt was not evaluable for efficacy analysis. Characteristics of the 29 evaluable pts were: median age 61 years (range, 35-79); 57% male; FLIPI low-41%, int-24%, high-35%, FLIPI2 low-24%, int-48%, high-28%; and median prior therapies 1 (range, 1-4). All pts previously received rituximab, median number of prior doses was 6 (range, 2-22), 69% had prior chemotherapy or chemoimmunotherapy, 41% combination biologic therapy, 21% maintenance rituximab, 7% radioimmunotherapy, and 3% single agent rituximab. The median number of CT-011 infusions administered was 10 (range, 1 – 12). The treatment was well tolerated with no therapy-related grade 3/4 toxicities, and no pt discontinued therapy due to toxicity. Of 29 pts eligible for efficacy analysis, 19 pts had an objective response for an ORR of 66%. CR was observed in 15 (52%) and PR in 4 (14%). Altogether, 25 (86%) pts had measurable tumor regression. Median time to response was 88 days. Of note, 17% of pts achieved initial response >3 mo from first treatment. After a median follow up of 14 mo, median PFS was 21.1 mo, and was not reached for the 19 responders or the 25 pts with measurable tumor regression. Clinical response was not significantly associated with FLIPI, FLIPI2, prior chemotherapy, number of prior rituximab doses, or duration of response to prior therapy (p>0.05). However, PFS was significantly associated with both FLIPI (median PFS for low/int versus high, not reached (NR) versus 12.65 mo; p=0.0056) and FLIPI2 (median PFS for low/int versus high, NR versus 13.47 mo; p=0.0344).

Conclusions: The combination of CT-011 (pidilizumab) and rituximab was active and well tolerated in pts with relapsed FL. The ORR of 66% and CR rate of 52% compare favorably with the previously reported ORR of 40% and CR rate of 11% with rituximab retreatment in relapsed FL. These data support further evaluation of PD-1 targeted therapy in FL.